Parkinson's disease (PD) is a disabling neurodegenerative disorder that is expected to affect as many as 1,000,000 Americans this year. Human and animals studies have shown that parkinsonism results from the degeneration of nigrostriatal dopaminergic neurons. Currently, treatment strategies for PD patients are limited. Gaining a better understanding of how striatal function is altered by the disease should broaden the range and efficacy of treatments. In the last funding period we focused on how dopamine and acetylcholine modulate the properties of voltage dependent ion channels in identified normosensitive striatal neurons. These studies have provided fundamental new insights into how these neuromodulators control the excitability of striatal neurons. Now, we are in a position to take the next step toward understanding the pathophysiology of PD - namely, how does the depletion of intrastriatal dopamine alter striatal function? Simply stated, our central goals are 1) to determine how DA depletion alters the regulation of voltage-dependent ion channels in striatal medium spiny neurons and 2) to determine how this adaptation alters their integrative, state-dependent behavior. To this end, we will determine how DA depletion alters Na+ and Ca2+ currents and their modulation by D2 (Specific Aim 1) and D1 receptor activation (Specific Aim 2) in identified striatal neurons. These experiments will rely upon voltage-clamp and single cell reverse transcription-polymerase chain reaction (scRT-PCR) approaches in acutely isolated striatal neurons - techniques with which we have an established track record. The proposed studies will employ newly developed mouse transgenic models in which striatal dopamine levels are profoundly reduced, mimicking the state found in advanced PD. Adaptations in the signal transduction pathways linking receptors to channels will be characterized using a combination of pharmacological, molecular and transgenic strategies. Inferences drawn from this work about adaptations in the mechanisms governing state transitions and repetitive spike activity will be explicitly tested using current- and voltage-clamp techniques in a novel corticostriatal slice preparation where medium spiny neurons exhibit state-dependent behavior resembling that seen in vivo (Specific Aim 3).